Biology subjects

Clayton, K.

Publications and source records attributed to Clayton, K..

6 recordsLinked to original sources

bioRxiv2023

Cortical contributions to the perception of loudness and hyperacusis

Sound perception is closely linked to the spatiotemporal patterning of neural activity in the auditory cortex (ACtx). Inhibitory interneurons sculpt the patterns of excitatory ACtx pyramidal neuron activity, and thus play a central role in sculpting the perception of sound. Reduced inhibition from parvalbumin-expressing (PV) inhibitory interneurons and the associated increased gain of sound-evoked pyramidal neuron spike rates are well-established consequences of aging and sensorineural hearing loss. Here, we reasoned that changes in PV-mediated inhibition would directly impact the perception of loudness. We hypothesized that ACtx PV activity could function as a perceptual volume knob, where reduced or elevated PV activity would increase or decrease the perceived loudness of sound, respectively. To test these hypotheses, we developed a two-alternative forced-choice loudness classification task for head-fixed mice and demonstrated that noise-induced sensorineural hearing loss directly caused a [~]10 dB loudness hyperacusis that begins hours after noise-induced sensorineural hearing loss and persists for at least several weeks. Conversely, sounds were perceived as [~]10 dB softer during optogenetic activation of ACtx PV neurons without having any effect on the overall detectability of sound. These data suggest that ACtx PV neurons can bi-directionally control the perceived loudness of sound, presumably via the strength of their inhibition onto local pyramidal neurons. Further, these data identify cortical PV neurons as a target for hyperacusis therapies and demonstrate a direct link between acquired sensorineural hearing loss and loudness hyperacusis.

neuroscience↗

bioRxiv2022

Neural signatures of auditory hypersensitivity following acoustic trauma

Throughout the brain, neurons exhibit a remarkable capacity to maintain stable firing rates despite large perturbations in afferent activity levels. As an exception, homeostatic regulation of neural activity often fails in the adult auditory system after hearing loss. Cochlear deafferentation caused by aging or noise exposure triggers widespread neural hyperactivity, particularly in the auditory cortex (ACtx), which underlies perceptual disorders including tinnitus and hyperacusis. Here, we show that mice with noise-induced damage of the high-frequency cochlear base were behaviorally hypersensitive to spared mid-frequency tones and to direct optogenetic stimulation of auditory thalamocortical neurons. Chronic 2-photon calcium imaging from ACtx pyramidal neurons (PyrNs) revealed an initial stage of diffuse hyperactivity, hypercorrelation, and hyperresponsivity that consolidated around deafferented map regions three or more days after acoustic trauma. Deafferented PyrN ensembles displayed hypersensitive decoding of spared mid-frequency tones, mirroring behavioral hypersensitivity. At the level of individual PyrNs, some exhibited stable, homeostatic gain control after acoustic trauma, while others showed non-homeostatic excess gain. Interestingly, factors such as baseline spontaneous activity levels and sound level encoding could account for 40% of the variability in PyrN gain regulation after acoustic trauma. These findings suggest that non-homeostatic regulation of cortical sound intensity coding following sensorineural loss may underlie the well-established clinical phenomenon of loudness hypersensitivity. Further, while cortical gain changes are triggered by reduced bottom-up afferent input, their subsequent stabilization is also shaped by their local circuit milieu, where baseline response features can identify neurons with the greatest propensity for developing pathological hyperactivity following sensorineural hearing loss.

neuroscience↗

bioRxiv2022

Rank Selection Genetic Algorithm optimises robust parameter estimation for systems biology models

The ability to reliably predict and infer cellular responses to environmental exposures would offer a major advance in the investigation of immune regulation in health and disease. One possible approach is the use of in silico modelling. Design of such a mathematical kinetic model would be based on existing knowledge of a biological system and utilise a partial data set to parameterise. However, the process of parameter estimation, key for the accuracy of the model, is difficult to conduct by hand, and thus a computational alternative is necessary. We report the utility of Genetic Algorithm with Rank Selection (GARS) as a parameter estimation tool on multiple biological models, including heat shock, signal transduction via ERK, circadian rhythm and NF{kappa}B systems, where it showed strong accuracy and superiority to the Extended Kalman Filter method, Algebraic Difference Equations, and MATLAB fminsearch approaches. GARS parameter estimation is a valuable tool for biological data because it reliably infers system behaviour from partial data sets, allowing for the prediction of cellular responses to environmental exposures.

systems biology↗

bioRxiv2021

TNF signalling fine-tunes Langerhans cell transcriptional programmes mediating adaptive immunity.

Langerhans cells (LCs) reside in the epidermis as a dense network of immune system sentinels, coordinating both immunogenic and tolerogenic immune responses. To determine molecular switches directing induction of LC immune activation, we performed mathematical modelling of gene regulatory networks identified by single cell RNA sequencing of LCs exposed to TNF, a key pro-inflammatory signal produced by the skin. Our approach delineated three programmes of LC phenotypic activation (immunogenic, tolerogenic or ambivalent), and confirmed that TNF enhanced LC immunogenic programming. Through regulon analysis followed by mutual information modelling, we identified IRF1 as the key transcription factor for the regulation of immunogenicity in LCs. Application of a mathematical toggle switch model, coupling IRF1 with tolerance-inducing transcription factors, determined the key set of transcription factors regulating the switch between tolerance and immunogenicity, and correctly predicted LC behaviour in LCs derived from different body sites. Our findings provide a mechanistic explanation of how combinatorial interactions between different transcription factors can coordinate specific transcriptional programmes in human LCs, interpreting the microenvironmental context of the local tissue microenvironments.

systems biology↗

bioRxiv2019

Single cell transcriptomic analysis identifies Langerhans cells immunocompetency is critical for IDO1- dependent ability to induce tolerogenic T cells.

Human epidermal Langerhans cells (LCs) can coordinate both immunogenic and tolerogenic immune responses, creating an attractive opportunity for immunomodulation strategies. To investigate transcriptional determinants of human primary LC tolerance we applied single cells RNA-sequencing combined with transcriptional network modelling and functional analysis. Unsupervised clustering of single cell transcriptomes revealed that steady-state LCs exist in immature and immunocompetent states, and become fully immunocompetent on migration. Interestingly, LC migration, which has been shown to result in upregulation of the transcription factor IRF4, led in parallel to increased expression of a tolerogenic gene module including IDO1, LGALS1, LAMTOR1 and IL10RA, which translated to efficient induction of regulatory T cells in co-culture assays by immunocompetent LCs. Using protein expression analysis and perturbation with inhibitors, we confirmed the role of IDO1 as a mediator of LC tolerogenic responses induced during LC migration. Computational analysis of regulons and Partial Information Decomposition analyses identified IRF4 as a key driver for LC tolerogenic programmes. The predicted IRF4-regulated genes were confirmed by analysis of CRISPR-Cas9 edited LCs. These findings suggest that efficient priming of tolerogenic responses by LCs requires upregulation of a migration-coupled maturation program which is superimposed with a tolerance-inducing genomic module.

systems biology↗

bioRxiv2019

Genomic programming of antigen cross-presentation in IRF4-expressing human Langerhans cells

Langerhans cells (LCs) in the epidermis present MHC I and MHC II-restricted antigens thereby priming either CD8 or CD4 T cell immune responses. The genomic programs and transcription factors regulating antigen presentation in LCs remain to be elucidated. We show human LCs are highly efficient in MHC I-antigen cross-presentation but lack the transcription factor IRF8 that is critical in dendritic cells. LC migration from the epidermis enhances their ability to cross-present antigens and is accompanied by the induction of the transcription factor IRF4, whose expression is correlated by scRNA-seq with genes involved in ubiquitin-dependent protein degradation. Chromatin profiling reveals enrichment of EICE and AICE composite DNA binding motifs in regulatory regions of antigen-presentation genes, which can be recognized by IRF4 in conjunction with PU.1 or BATF3 expressed in LCs. Thus, the genomic programming of human LCs including inducible expression of IRF4 with enhanced cross-presentation distinguishes them from conventional dendritic cells.

immunology↗